Nishikawa K, Linsley P S, Collins A B, Stamenkovic I, McCluskey R T, Andres G
Department of Pathology, Massachusetts General Hospital, Boston.
Eur J Immunol. 1994 Jun;24(6):1249-54. doi: 10.1002/eji.1830240602.
The interaction of the T cell receptor with the antigen/major histocompatibility class II complex is insufficient to induce optimal T cell activation. Co-stimulatory signals, including those provided by CD28/CTLA-4 on T cells and B7 molecules (B7-1, -2, and -3) on antigen-presenting cells, are also required. CD28-B7 interactions can be blocked by a soluble human CTLA-4 chimeric protein (CTLA4Ig). We tested the effect of administration of CTLA4Ig on experimental anti-glomerular basement membrane (GBM) autoimmune glomerulonephritis in Wistar-Kyoto rats induced by immunization with bovine GBM. The disease is characterized by development of antibody to the alpha 3 chain of type IV collagen (Goodpasture's antigen), deposition of rat IgG in GBM, infiltration of the kidney by T cells and macrophages, severe crescent formation and renal failure leading to death in 5-6 weeks. Animals injected with human CTLA4Ig from day 0 to day 14 or to day 35 had reduced disease severity. Beneficial effects were observed even when injections were begun after the onset of glomerulonephritis on day 14. However, the rats developed antibody to the human CTLA4Ig, associated with reduction in levels of circulating CTLA4Ig. The results provide evidence for CD28/CTLA-4 signaling in rat autoimmune glomerulonephritis, and suggest that more effective inhibition of B7-dependent T cell activation, such as might be achieved with homologous CTLA4Ig, could be useful in the treatment of autoimmune diseases.
T细胞受体与抗原/主要组织相容性复合体II类分子的相互作用不足以诱导最佳的T细胞活化。还需要共刺激信号，包括T细胞上的CD28/CTLA-4和抗原呈递细胞上的B7分子（B7-1、-2和-3）提供的信号。CD28-B7相互作用可被可溶性人CTLA-4嵌合蛋白（CTLA4Ig）阻断。我们测试了给予CTLA4Ig对用牛肾小球基底膜（GBM）免疫诱导的Wistar-Kyoto大鼠实验性抗GBM自身免疫性肾小球肾炎的影响。该疾病的特征是产生针对IV型胶原α3链（Goodpasture抗原）的抗体、大鼠IgG在GBM中的沉积、T细胞和巨噬细胞浸润肾脏、严重新月体形成以及肾衰竭，导致5-6周内死亡。从第0天到第14天或到第35天注射人CTLA4Ig的动物疾病严重程度降低。即使在肾小球肾炎于第14天发病后开始注射，也观察到了有益效果。然而，大鼠产生了针对人CTLA4Ig的抗体，这与循环CTLA4Ig水平降低有关。这些结果为大鼠自身免疫性肾小球肾炎中的CD28/CTLA-4信号传导提供了证据，并表明更有效地抑制B7依赖性T细胞活化，如使用同源CTLA4Ig可能实现的那样，可能对自身免疫性疾病的治疗有用。
